Genetic mechanisms of arterial stiffness in polygenic salt-sensitive hypertension

描述（由申请人提供）：我们的长期目标是阐明原发性或多基因高血压的病因，重点是阐明高血压易感性背后的遗传变异以及加剧高血压易感性和终末器官疾病的基因-环境相互作用。在临床研究中，以脉搏波速度或 PWV 测量的动脉硬化的重要性日益凸显，证明了 PWV 增加与心血管结局（中风、冠心病和慢性肾病）之间的关联，这已经确定了一个可能可靠的预测参数，但同时也强调了通过动物模型研究来解决机制的必要性。因此，本研究提案重点关注 RFA 规定的目标：#1）“在动物模型中探索动脉硬化与高血压发展之间的时间关系”，#2）“对（原发性/多基因）高血压背景下导致导管动脉硬化的机制进行细胞和分子研究”。为了实现这一目标，我们优先考虑以下具体目标： 目标 1. 在雄性和雌性有中风倾向的 Dahl S 大鼠中，检查大动脉硬化（通过高分辨率超声检查测量主动脉 PWV 和应变、颈动脉 PWV 和应变）与盐敏感性高血压（通过 SBP、DBP、MAP 和 PP 的非应激 24/7 遥测血压分析测量）和中风之间的时间关系。目标 2. 定义所有三个血管层中主动脉和颈动脉结构的时间和空间变化，以及在高血压及其终末器官并发症过程中钠引起的动脉僵硬度恶化和进展的推定基因表达变化。目标 3. 通过对 F2[Dahl S x Dahl R] 杂交雄性和雌性大鼠进行全基因组扫描，识别单独或交互导致动脉僵硬的常见和性别特异性数量性状位点 (QTL)，阐明多基因盐敏感性高血压背景下动脉僵硬度的遗传机制的作用。总之，这三个目标将阐明钠诱导的易发生中风的高血压大鼠模型中主动脉和颈动脉僵硬度与多基因（原发性）高血压和中风的关系，并深入了解因果细胞、分子和遗传机制。

DESCRIPTION (provided by applicant): Our long term goal is to elucidate the etiology of essential or polygenic hypertension with a focus on the elucidation of genetic variants that underlie hypertension susceptibility and gene-environment interactions which exacerbate hypertension susceptibility and end-organ disease. The emerging importance of arterial stiffening measured as pulse wave velocity or PWV in clinical studies demonstrating the association of increased PWV and cardiovascular outcomes (stroke, coronary heart disease, and chronic kidney disease) has pinpointed a likely robust predictive parameter, but at the same time highlighted the need for animal model studies to address mechanisms. Accordingly, this research proposal focuses on RFA-stated goals: #1) "to explore the temporal relationship between arterial stiffening and the development of hypertension in an animal model", and #2) to conduct "cellular and molecular investigation of mechanisms that lead to conduit artery stiffening in the context of (essential/polygenic) hypertension". To accomplish this we have prioritized the following specific aims: Aim 1. Examine the temporal relation between large artery stiffening (measured as aortic PWV and strain, carotid PWV and strain via high-resolution ultrasonography), and the development of salt-sensitive hypertension (measured via non-stress 24/7 telemetric BP analysis of SBP, DBP, MAP and PP) and stroke in both male and female stroke-prone Dahl S rats. Aim 2. Define the temporal and spatial changes in aortic and carotid artery structure in all three vessel layers, along with putative gene expression changes that underlie Na-induced exacerbation and progression of arterial stiffness along the disease course of hypertension and its end-organ complications. Aim 3. Elucidate the role of genetic mechanisms in the causation of arterial stiffness in the context of polygenic salt-sensitive hypertension via genome-wide scan of F2[Dahl S x Dahl R]-intercross male and female rats identifying common and sex-specific quantitative trait loci (QTLs) that contribute to arterial stiffness individually or interactively. Altogether, these three aims will elucidate the relationship of aortic and carotid arterial stiffness to polygenic (essential) hypertension and stroke in a Na-induced stroke-prone hypertension rat model, as well as give insight into causal cellular, molecular, and genetic mechanisms.